Field of the Invention
[0001] The invention encompasses dry compression pharmaceutical compositions of aripiprazole,
methods of making tablets from the compositions, and tablets of the dry compression
pharmaceutical composition.
Background of the invention
[0002] Aripiprazole, as reported in the literature, can exist in multiple crystal forms.
For example, PCT publication
WO 03/026659 describes at least nine crystal forms, including an hydrate and anhydrous forms,
such as Type-I and Type-II. According to
WO 03/026659, the procedures disclosed in Proceedings of the 4th Japanese-Korean Symposium on
Separation Technology (October 6-8, 1996) yield significantly hydroscopic crystalline
forms. The procedures disclosed in the Proceedings yield Type-I crystals of aripiprazole
anhydride, prepared by recrystallizing from an ethanol solution of aripiprazole, or
by heating aripiprazole hydrate at 80°C. The same Proceedings disclose that Type-II
crystals of aripiprazole anhydride can be prepared by heating Type-I crystals of aripiprazole
anhydride at 130°C to 140°C for 15 hours. In addition to Type-I and Type-II crystals,
several additional anhydrous crystal forms are known. PCT publication
WO 03/026659 discloses anhydride crystals Form B, C, D, E, F, or G and a hydrate form denominated
Form A.
[0003] As reported in
WO 03/026659, the multiple polymorphs may interconvert from one to the other. For instance,
WO 03/026659 discloses that if the anhydrous form is exposed to moisture, then it may take on
water and convert into a hydrous form. As stated in
WO 03/026659, this presents several disadvantages, for instance the compound may be less bioavailable
and less soluble. The hygroscopicity of aripiprazole crystals makes them difficult
to handle since costly and burdensome measures must be taken to ensure that the crystals
are not exposed to moisture during process and formulation. Despite these concerns,
WO 03/026659 discloses a wet granulation process for preparing pharmaceutical compositions using
aripiprazole anhydride and various carriers.
[0004] Other novel crystal aripiprazole forms are disclosed in PCT publication
WO 05/058835. These other forms include Form I, II, VII, VIII, X, XI, XII, XIV, XIX, and XX.
[0005] Polymorphic transformations may be undesirable during pharmaceutical composition
preparation or formulation. Hydration or manipulation of polymorphs may induce such
unwanted polymorphic transformations. Also, the use of some aripiprazole polymorphs
in pharmaceutical tablets may potentially induce unwanted polymorphic transformations,
which in turn may reduce the bioavailability of the drug. Therefore, it would be desirable
to develop aripiprazole formulations in which there is no potential of hydration and/or
possible polymorphic interconversions.
Summary of the invention
[0006] One embodiment of the invention encompasses a method of making an aripiprazole formulation
comprising providing a mixture of aripiprazole, at least one diluent, at least one
tablet binder, and at least one tablet disintegrant; blending the mixture to obtain
a homogeneous mixture; optionally adding at least one tablet lubricant to the homogeneous
mixture; and dry compressing the homogeneous mixture into the formulation. The formulation
may be tablets, slugs or a compact. The method may further comprise milling the slug
or compact into a granulate, adding at least one tablet lubricant to the granulate,
and dry compressing the granulate into a tablet. The mixture may further comprise
a colorant.
[0007] Preferably, the aripiprazole may be at least one of anhydrous aripiprazole Type-I,
Type-II, or Form II. In one particular embodiment, the aripiprazole may have a particle
size distribution where d(0.9) is about 300 µm or less. The tablet may have a dissolution
rate where not less than 80% of the initial aripiprazole is dissolved after about
30 minutes. Preferably, the tablet may have a dissolution rate where not less than
85% of the initial aripiprazole is dissolved after about 30 minutes, and more preferably
not less than 90%, as tested under the conditions described below.
[0008] In another embodiment, the diluent is calcium carbonate, calcium phosphate (dibasic
and/or tribasic), calcium sulfate, powdered cellulose, dextrates, dextrin, fructose,
kaolin, lactitol, anhydrous lactose, lactose monohydrate, maltose, mannitol, microcrystalline
cellulose, sorbitol, sucrose, or starch. Preferably, the diluent is lactose monohydrate,
microcrystalline cellulose, or starch. In one particular embodiment, the diluent is
present in an amount of about 35% to about 85% by weight of the tablet.
[0009] In another embodiment, the binder is acacia, alginic acid, carbomer, sodium carboxymethylcellulose,
dextrin, ethylcellulose, gelatin, glucose, guar gum, hydroxypropyl cellulose, maltose,
methylcellulose, polyethylene oxide, or povidone. Preferably, the binder is hydroxypropyl
cellulose. In one particular embodiment, the binder is present in an amount of about
0.5% to about 5% by weight of the tablet.
[0010] In yet another embodiment, the disintegrant is alginic acid, sodium croscarmellose,
crospovidone, maltose, microcrystalline cellulose, potassium polacrilin, sodium starch
glycolate, or starch. Preferably, the disintegrant is crospovidone, sodium starch
glycolate or sodium croscarmellose. In one particular embodiment, the disintegrant
is present in an amount of about 3% to about 15% by weight of the tablet.
[0011] In yet another embodiment, the lubricant is calcium stearate, glyceryl behenate,
magnesium stearate, mineral oil, polyethylene glycol, sodium stearyl fumarate, stearic
acid, talc, or zinc stearate. Preferably, the lubricant is magnesium stearate. In
one particular embodiment, the lubricant is present in an amount of about 0.5% to
about 2% by weight of the tablet.
[0012] In one embodiment, the invention encompasses a tablet comprising: aripiprazole Type-I,
lactose monohydrate, starch, microcrystalline cellulose, hydroxypropyl cellulose,
and magnesium stearate.
[0013] In another embodiment, the invention encompasses a tablet comprising aripiprazole
Type-II, lactose monohydrate, starch, microcrystalline cellulose, hydroxypropyl cellulose,
color red, and magnesium stearate.
[0014] In yet another embodiment, the invention encompasses a tablet comprising aripiprazole
Form II, lactose monohydrate, starch, microcrystalline cellulose, hydroxypropyl cellulose,
sodium starch glycolate, color red, and magnesium stearate.
Brief Description of the Figures
[0015]
Figure 1 illustrates the x-ray diffraction pattern of aripiprazole Type-I.
Figure 2 illustrates the x-ray diffraction pattern of aripiprazole Type-II.
Detailed Description of the Invention
[0016] The problems associated with the hydration of aripiprazole during formulation or
storage have focused research into developing stable anhydrous forms of aripiprazole.
These forms would be less or non-hygroscopic, and thus resistant to hydration and
the accompanying possible polymorphic transformation. The present invention provides
an alternative to the development of stable anhydrous forms of aripiprazole. The present
invention encompasses dry formulations of aripiprazole and methods of making tablets
using the dry formulations in direct compression or dry granulation via dry compaction.
These dry formulations and the methodology associated with such dry formulations prevent
or reduce hydration and the associated subsequent polymorphic transformations.
[0017] Thus, the present invention encompasses methods of making tablets by compression
of dry formulations and tablets made using dry compression methodology. There are
economic advantages in the dry compression of formulations over wet granulation, because
the dry compression requires fewer unit operations. Using less equipment, lower power
consumption, less space, less time, and less labor are a few examples of how the methodology
reduces production cost of tablets. Also, dry compression avoids the use of organic
solvents during the preparation of the formulations. Organic solvents may be either
toxic or difficult to dispose of because of environmental concerns.
[0018] Dry compression, however, is generally limited to those circumstances in which the
active ingredient has physical characteristics suitable for forming pharmaceutically
acceptable tablets. These physical characteristics include, but are not limited to,
good flowing properties, compressibility, and compactability.
[0019] Dry compression formulations comprising aripiprazole were developed, because it was
found that aripiprazole crystals were suitable for dry compression formulations. In
particular, it was found that anhydrous aripiprazole crystals were suitable for dry
compression formulations. As used herein with the term "aripiprazole," the term "anhydrous"
means aripiprazole is crystallized in a form, which does not contain solvent of crystallization
or water incorporated within the crystal lattice, but may include water outside the
crystal lattice.
[0020] The method of making an aripiprazole formulation comprises providing a mixture of
aripiprazole, at least one diluent, at least one tablet binder, and at least one tablet
disintegrant; blending the mixture to obtain a homogeneous mixture; optionally adding
at least one tablet lubricant to the homogeneous mixture; and dry compressing the
homogeneous mixture into the formulation. The formulation can be in the shape of a
tablet, a slug, or a compact. The method may further comprise milling the slug or
compact into a granulate, adding at least one tablet lubricant to the milled granulate,
and dry compressing the milled granulate into a tablet. Optionally, at least one colorant
may be added to the mixture to provide any desired colored tablet.
[0021] The blending step is carried out to substantially homogeneous mixture. The skilled
artisan with little or no experimentation can easily determine the equipment and conditions
necessary for the blending steps. Factors that may influence the blending step include,
but are not limited to, the amount of materials, the physical characteristics of the
materials, the equipment, and the speed of mixing.
[0022] The dry compressing step includes compressing the homogeneous mixture into a formulation.
The formulation may be shaped as tablets, ribbons or blocks of solid material, or
slugs. When the formulation is shaped as ribbons or blocks of solid material, or slugs,
the ribbons or blocks of solid material, or slugs are milled. Thereafter, the milled
material or granulate is blended with extragranular excipients and compressed into
tablets. The compressing step may be carried out using a tablet compression apparatus
commonly used in tableting or other suitable equipment to make slugs, ribbons, or
blocks of solid material. For example, a Kilian tableting press may be used to form
the tablets.
[0023] Any aripiprazole may be used in the formulation and method of the invention. Typically,
anhydrous aripiprazole may be used in the dry compression or dry granulation formulation.
Preferably, the anhydrous aripiprazole is at least one of Type-I, Type-II, or Form
II. Type-I aripiprazole may be prepared by crystallization in ethanol and drying according
to method described in
WO 2005/058835. Alternatively, Type-I aripiprazole may be made according to the Reference Examples
of
WO 03/026659 and as described in the Proceedings of the 4
th Japanese-Korean Symposium on Separation Technology (October 6-8, 1996), both references
hereby incorporated by reference. Type-II may be obtained by heating Type-I crystals
of aripiprazole anhydride at 140°C for 15 hours, according to the Reference Examples
disclosed
WO 03/026659. Form II aripiprazole may be prepared as disclosed in
WO 05/058835.
[0024] Type-I aripiprazole is characterized by x-ray diffraction peaks at 8.8, 10.6, 11.1,
12.1, 15.0, 15.8, 17.7, 20.4, 22.1, and 29.8 ± 0.2 degrees 2-theta. Type-II aripiprazole
is characterized by x-ray diffraction peaks at 10.1, 11.7, 13.9, 15.1, 18.2, 20.8,
21.8, 23.5, 23.8, and 28.9 ± 0.2 degrees 2-theta. The XRD diffractograms of aripiprazole
Type-I and Type-II are shown in figures 1 and 2, respectively. Form II aripiprazole
is characterized by x-ray diffraction peaks at 16.5, 18.7, 21.9, 22.4, and 23.5 ±
0.2 degrees 2-theta.
[0025] The crystal form of aripiprazole within the pharmaceutical compositions may be monitored
using known state of the art techniques. For example, techniques such as X-ray powder
diffraction (XRD) or solid-state NMR of carbon-13, nitrogen-14, or chlorine, among
others, may be used. Generally, any instrumentation of X-Ray powder diffraction or
solid-state NMR normally available in laboratories is suitable for monitoring the
crystal forms of aripiprazole in pharmaceutical compositions. Typical methods for
obtaining X-ray diffractions of aripiprazole may be found in
WO 03/026659 or
WO 05/058835.
[0026] Optionally, the aripiprazole may have a particle shape. Typically, the particle size
distribution d(0.9) is about 300 µm or less. If aripiprazole Type-I or Type-II is
used, the particle size distribution d(0.9) is about 180 µm to about 270 µm. If aripiprazole
Form II is used, the particle size distribution d(0.9) is about 25 µm.
[0027] The single dose of the active ingredient is small, and an inert substance may be
added to increase the bulk and make the tablet a practical size for compression. Diluents
are used for this purpose. Diluents used in the mixture include diluents commonly
used for tablet preparation. For example, diluents include, but are not limited to,
calcium carbonate, calcium phosphate (dibasic and/or tribasic), calcium sulfate, powdered
cellulose, dextrates, dextrin, fructose, kaolin, lactitol, anhydrous lactose, lactose
monohydrate, maltose, mannitol, microcrystalline cellulose, sorbitol, sucrose, or
starch. Preferably, the diluent is lactose monohydrate, microcrystalline cellulose,
or starch. Typically, the diluent is present in an amount of about 35% to about 85%
by weight of the tablet. Preferably, the diluent is present in an amount of about
40% to about 80% by weight of the tablet.
[0028] Binders are agents used to impart cohesive qualities to the powdered material. Binders
impart a cohesiveness to the tablet formulation that ensures that the tablet remains
intact after compression. Tablet binders used in the mixture include tablet binders
commonly used for tablet preparation. Tablet binders include, but are not limited
to, acacia, alginic acid, carbomer, sodium carboxymethylcellulose, dextrin, ethylcellulose,
gelatin, glucose, guar gum, hydroxypropyl cellulose, maltose, methylcellulose, polyethylene
oxide, or povidone. Preferably, the tablet binder is hydroxypropyl cellulose. Typically,
the tablet binder is present in an amount of about 0.5% to about 5% by weight of the
tablet. Preferably, the tablet binder is present in an amount of about 0.7% to about
3% by weight of the tablet.
[0029] A disintegrant is a substance or mixture of substances added to a tablet formulation
to facilitate a tablet's breakup or disintegration after tablet administration. The
aripiprazole should be released from the tablet as efficiently as possible to allow
dissolution. Tablet disintegrants used in the mixture include, but are not limited
to, alginic acid, sodium croscarmellose, crospovidone, maltose, microcrystalline cellulose,
potassium polacrilin, sodium starch glycolate, or starch. Preferably, the tablet disintegrant
is a "super-disintegrant:" crospovidone, sodium starch glycolate or sodium croscarmellose.
Typically, the tablet disintegrant is present in an amount of about 3% to about 15%
by weight of the tablet. Preferably, the tablet disintegrant is present in an amount
of about 5% to about 10% by weight of the tablet.
[0030] Lubricants have a number of functions in tablet manufacturing. For example, lubricants
prevent adhesion of the tablet material to equipment, reduce interparticle friction,
and facilitate the ejection of the tablet from the die cavity, among others. Tablet
lubricants added to the homogeneous mixture include those typically used in tablet
formulations. Tablet lubricants include, but are not limited to, calcium stearate,
glyceryl behenate, magnesium stearate, mineral oil, polyethylene glycol, sodium stearyl
fumarate, stearic acid, talc, or zinc stearate. Preferably, the tablet lubricant is
magnesium stearate. Typically, the tablet lubricant is present in an amount of about
0.5 to about 2 percent by weight of the tablet. Preferably, the tablet lubricant is
present in an amount of about 0.7 to about 1 percent by weight of the tablet.
[0031] In one embodiment, the dry compression pharmaceutical formulation of the invention
has a dissolution rate where not less than 80% of the initial aripiprazole is dissolved
after about 30 minutes. Preferably, the tablet may have a dissolution rate where not
less than 85% of the initial aripiprazole is dissolved after about 30 minutes, and
more preferably not less than 90%.
[0032] Once a tablet was made using the methodology described above, the aripiprazole was
tested to determine whether a polymorphic transformation had occurred. The x-ray diffraction
pattern of the aripiprazole within the pharmaceutical composition made in Example
1 had peaks at 8.8, 10.6, 11.1, 12.1, 15.0, 15.8, 17.7, 22.1, and 29.8 ± 0.2 degrees
2-theta. The x-ray diffraction pattern of the aripiprazole within the pharmaceutical
composition made in Example 2 had peaks at 10.1, 11.7, 14.0, 15.1, and 21.9 ± 0.2
degrees 2-theta. A comparison of the x-ray diffraction patterns of the aripiprazole
of Examples 1 and 2 with the x-ray diffraction patterns with aripiprazole Type-I and
Type-II, respectively, demonstrated that the tablet obtained by dry compression of
the dry aripiprazole formulation did not include other polymorphic aripiprazole forms,
including hydrates.
[0033] The invention also encompasses tablets made using the methodology described above.
In one embodiment the tablet comprises aripiprazole, lactose monohydrate, starch,
microcrystalline cellulose, hydroxypropyl cellulose, and magnesium stearate. Optionally,
the tablet may further comprise a colorant. In another embodiment the tablet comprises
aripiprazole Type-I, lactose monohydrate, starch, microcrystalline cellulose, hydroxypropyl
cellulose, and magnesium stearate. In a preferred embodiment the tablet comprises
aripiprazole Type-I (30 mg/tablet), lactose monohydrate (120 mg/tablet), starch (60
mg/tablet), microcrystalline cellulose (60 mg/tablet), hydroxypropyl cellulose (8
mg/tablet), and magnesium stearate (2 mg/tablet).
[0034] In yet another embodiment the invention encompasses a tablet comprising aripiprazole
Type-II, lactose monohydrate, starch, microcrystalline cellulose, hydroxypropyl cellulose,
color red, and magnesium stearate. In a preferred embodiment, the invention encompasses
a tablet comprising aripiprazole Type-II (30 mg/tablet), lactose monohydrate (120
mg/tablet), starch (60 mg/tablet), microcrystalline cellulose (60 mg/tablet), hydroxypropyl
cellulose (8 mg/tablet), color red (0.06 mg/tablet), and magnesium stearate (2 mg/tablet).
[0035] Another embodiment the invention encompasses a tablet comprising aripiprazole Form
II, lactose monohydrate, starch, microcrystalline cellulose, hydroxypropyl cellulose,
sodium starch glycolate, color red, and magnesium stearate. Preferably, the tablet
comprises aripiprazole Form II (30 mg/tablet), lactose monohydrate (112 mg/tablet),
starch (60 mg/tablet), microcrystalline cellulose (94 mg/tablet), hydroxypropyl cellulose
(2 mg/tablet), sodium starch glycolate (10 mg/tablet), color red (0.06 mg/tablet),
and magnesium stearate (2 mg/tablet).
[0036] In a preferred embodiment, the method comprises blending aripiprazole Type-I, lactose
monohydrate, starch, color red, hydroxypropyl cellulose, and magnesium stearate into
a mixture; dry granulating the mixture and compressing the granulated mixture into
slugs; milling the slugs and blending the milled slugs with microcrystalline cellulose
and magnesium stearate into a second mixture; compressing the second mixture into
tablets, wherein the tablets have a hardness range of about 9 to 15 Strong-Cobb units
and a friability of less than about 1%. Optionally, the aripiprazole Type-I has a
d(0.9) value of about 186 µm.
[0037] It is understood, of course, that some excipient materials can function as both diluent
and binder, or filler and disintegrant, and that some materials may exist that can
fulfill all three roles. There is no intention to limit the invention to methods only
using three distinct excipient materials "diluent," "tablet binder," and "tablet disintegrant,"
but rather the invention is directed to materials fulfilling these functions. For
example the material that is the "at least one diluent" also might be the same as
the material fulfilling the role of "at least one tablet binder" as long as the material
is present in sufficient amount to fulfill both functions.
[0038] Another embodiment the invention encompasses a tablet comprising aripiprazole Type
I, lactose monohydrate, starch, microcrystalline cellulose, hydroxypropyl cellulose,
color red, and magnesium stearate. Preferably, the tablet comprises aripiprazole Type
I (30 mg/tablet), lactose monohydrate (106.44 mg/tablet), starch (60 mg/tablet), microcrystalline
cellulose (81 mg/tablet), hydroxypropyl cellulose (3 mg/tablet), color red (0.06 mg/tablet),
and magnesium stearate (4.5 mg/tablet).
[0039] Having described the invention with reference to certain preferred embodiments, other
embodiments will become apparent to one skilled in the art from consideration of the
specification. The invention is further defined by reference to the following examples
describing in detail the formation of dry compression pharmaceutical formulations
of aripiprazole and the dissolution of the tablets made using the dry compression
pharmaceutical formulations. It will be apparent to those skilled in the art that
many modifications, both to materials and methods, may be practiced without departing
from the scope of the invention.
Examples
Example 1: Preparation of 30 mg Tablets Containing Aripiprazole Type-I Using Dry Compression
[0040] A mixture was made of aripiprazole Type-I (105 g), lactose monohydrate NF (420 g),
starch NF (210 g), microcrystalline cellulose NF (210 g), and hydroxypropyl cellulose
NF (28 g). The aripiprazole Type-I had a D(0,9) value of about 245 µm. The mixture
was blended for 20 minutes. Magnesium stearate NF (7 g) was sieved and added to the
blended mixture and blended for an additional 5 minutes. Thereafter, the mixture was
compressed into tablets using a Kilian tableting press to have a hardness range of
about 12 to 22 Strong-Cobb units and a friability of less than 1%.
Example 2. Preparation of 30 mg Tablets Containing Aripiprazole Type-II Using Dry
Compression
[0041] A mixture was made of aripiprazole Type-II (120 mg), lactose monohydrate NF (479.76
g), starch NF (240 g), microcrystalline cellulose NF (240 g), hydroxypropyl cellulose
NF (32 g), and color red (0.24 g). The aripiprazole Type-II had a D(0,9) value of
about 270 µm. The mixture was blended for 20 minutes. Magnesium stearate NF (8 g)
was sieved and added to the blended mixture and blended for an additional 5 minutes.
Thereafter, the mixture was compressed into tablets using a Kilian tableting press
to have a hardness range of about 8 to 21 Strong-Cobb units and a friability of less
than 1%.
Example 3. Preparation of 30 mg Tablets Containing Aripiprazole Form II Using Dry
Compression
[0042] A mixture was made of aripiprazole Form II (150 g), lactose monohydrate NF (559.7
g), starch NF (150 g), microcrystalline cellulose NF (470 g), hydroxypropyl cellulose
NF (10 g), sodium starch glycolate (50 g), and color red (0.3 g). The mixture was
blended for 20 minutes. Magnesium stearate NF (10 g) was sieved and added to the blended
mixture and blended for an additional 5 minutes. Thereafter, the mixture was compressed
into tablets using a Kilian tableting press to have a hardness range of about 5 to
25 Strong-Cobb units and a friability of less than 1%.
Example 4. Preparation of 30 mg Tablets Containing Aripiprazole Type I Using a Dry
Granulation Method
[0043] A mixture of aripiprazole Type-I (210 g), lactose monohydrate NF (745.08 g), starch
NF (420 g), color red (0.42 g), hydroxypropyl cellulose NF (21 g) and magnesium stearate
NF (15.75 g) was dry granulated. The aripiprazole Type-I had a D(0,9) value of about
186 µm. The mixture was compressed into slugs, the slugs were milled and blended with
extragranular excipients: microcrystalline cellulose NF (567 g) and magnesium stearate
NF (15.75 g). Thereafter, the mixture was compressed into tablets using a Kilian tableting
press to have a hardness range of about 9 to 15 Strong-Cobb units and a friability
of less than 1%.
Example 5: Dissolution Measurements of Tablets Made in Examples 1-4
[0044] The dissolution for tablets from each of the above-described examples was studied.
Typically, a the dissolution rate was measured for each batch after 30 minutes. The
dissolution was carried out using an USP apparatus II (paddle) at 60 rpm with 900
ml of 0.1 N HCl at a temperature of 37°C. The results are summarized in Table 1.
Table 1, Dissolution Measurement of Tablets from Examples 1-4 |
Example No. |
Time (minutes) |
Average Dissolution* |
Minimum Dissolution* |
1 |
30 |
95 |
90 |
2 |
30 |
85 |
80 |
3 |
30 |
87 |
81 |
4 |
30 |
98 |
96 |
* Average dissolution and minimum dissolution are reported as a percent by weight
of the labeled amount. |
1. A method of making an aripiprazole formulation comprising:
providing a mixture of aripiprazole, at least one diluent, at least one tablet binder,
and at least one tablet disintegrant;
blending the mixture to obtain a homogeneous mixture;
optionally adding at least one tablet lubricant to the homogeneous mixture; and
dry compressing the homogeneous mixture into the formulation.
2. The method according to claim 1, wherein the formulation is a tablet.
3. The method according to claim 1, the formulation is a slug or a compact.
4. The method according to claim 3, further comprising milling the slug or compact into
a granulate, adding at least one tablet lubricant to the granulate, and dry compressing
the granulate into a tablet.
5. The method according to any one of the preceding claims, wherein the mixture further
comprises a colorant.
6. The method according to any one of the preceding claims, wherein the aripiprazole
is at least one of anhydrous aripiprazole Type-I, Type-II, or Form II.
7. The method according to any one of the preceding claims, wherein the aripiprazole
has a particle size distribution d(0.9) of about 300 µm or less.
8. The method according to any one of the preceding claims, wherein the diluent is calcium
carbonate, calcium phosphate (dibasic and/or tribasic), calcium sulfate, powdered
cellulose, dextrates, dextrin, fructose, kaolin, lactitol, anhydrous lactose, lactose
monohydrate, maltose, mannitol, microcrystalline cellulose, sorbitol, sucrose, or
starch.
9. The method according to claim 8, wherein the diluent is lactose monohydrate, microcrystalline
cellulose, or starch.
10. The method according to any one of the preceding claims, wherein the diluent is present
in an amount of about 35 to about 85 percent by weight of the tablet.
11. The method according to any one of the preceding claims, wherein the binders is acacia,
alginic acid, carbomer, sodium carboxymethylcellulose, dextrin, ethylcellulose, gelatin,
glucose, guar gum, hydroxypropyl cellulose, maltose, methylcellulose, polyethylene
oxide, or povidone.
12. The method according to claim 11, wherein the binder is hydroxypropyl cellulose.
13. The method according to any one of the preceding claims, wherein the binder is present
in an amount of about 0.5 to about 5 percent by weight of the tablet.
14. The method according to any one of the preceding claims, wherein the disintegrant
is alginic acid, sodium croscarmellose, crospovidone, maltose, microcrystalline cellulose,
potassium polacrilin, sodium starch glycolate, or starch.
15. The method according to claim 14, wherein the disintegrant is crospovidone, sodium
starch glycolate or sodium croscarmellose.
16. The method according to any one of the preceding claims, wherein the disintegrant
is present in an amount of about 3 to about 15 percent by weight of the tablet.
17. The method according to any one of the preceding claims, wherein the lubricant is
calcium stearate, glyceryl behenate, magnesium stearate, mineral oil, polyethylene
glycol, sodium stearyl fumarate, stearic acid, talc, or zinc stearate.
18. The method according to claim 17, wherein the lubricant is magnesium stearate.
19. The method according to any one of the preceding claims, wherein the lubricant is
present in an amount of about 0.5 to about 2 percent by weight of the tablet.
20. The method according to any one of the preceding claims, wherein the tablet has a
dissolution rate where not less than 85% of the aripiprazole is dissolved after about
30 minutes.
21. The method according to claim 20, wherein the tablet has a dissolution rate where
not less than 85% of the initial aripiprazole is dissolved after about 30 minutes.
22. The method according to claim 21, wherein the tablet has a dissolution rate where
not less than 90% of the initial aripiprazole is dissolved after about 30 minutes.
23. A method of making an aripiprazole formulations comprising;
blending aripiprazole Type-I, lactose monohydrate, starch, color red, hydroxypropyl
cellulose, and magnesium stearate into a mixture;
dry granulating the mixture and compressing the granulated mixture into slugs;
milling the slugs and blending the milled slugs with microcrystalline cellulose and
magnesium stearate into a second mixture; and
compressing the second mixture into tablets,
wherein the tablets have a hardness range of about 9 to 15 Strong-Cobb units and a
friability of less than about 1%.
24. The method according to claim 23, wherein the aripiprazole Type-I has a d(0.9) value
of about 186 µm.
25. A tablet comprising: aripiprazole Type-I, lactose monohydrate, starch, microcrystalline
cellulose, hydroxypropyl cellulose, and magnesium stearate.
26. A tablet comprising aripiprazole Type-II, lactose monohydrate, starch, microcrystalline
cellulose, hydroxypropyl cellulose, color red, and magnesium stearate.
27. A tablet comprising aripiprazole Form II, lactose monohydrate, starch, microcrystalline
cellulose, hydroxypropyl cellulose, sodium starch glycolate, color red, and magnesium
stearate.
28. A dry formulation tablet containing aripiprazole.
29. The dry formulation tablet according to claim 28, wherein the tablet has a dissolution
rate where not less than 90% of the initial aripiprazole is dissolved after about
30 minutes.
30. A dry formulation tablet containing anhydrous aripiprazole.